Riddle Me This: Acalculous Cholecystitis as an Unusual Complication of Immunoglobulin M Negative Mononucleosis

Infectious mononucleosis is a common disease of the adolescent caused by the Epstein-Barr virus (EBV). We present a rare case of a male adult with acalculous cholecystitis due to infectious mononucleosis. A correct diagnosis was challenging due to a false negative antibody test. Laboratory values were significant for a marked lymphocytosis and an early Immunoglobulin G (IgG) response without initial Immunoglobulin M (IgM) elevation. However, IgM antibodies were elevated two weeks later. Symptoms resolved quickly under symptomatic therapy. Antibody level patterns in asplenic patients with infectious mononucleosis are characterized by an atypical course with a delayed rise in IgM antibodies, which complicates the correct diagnosis of an EBV-induced acalculous cholecystitis.


Introduction
Infectious mononucleosis is a common disease of the adolescent caused by the Epstein-Barr virus (EBV), a widely disseminated herpes virus (Type IV). Frequent symptoms are fatigue and dysphagia while clinical signs include fever, adenopathy, pharyngitis, and atypical lymphocytosis [1]. Diagnosis is usually established by clinical signs and supported by antibody detection. The latter can be misleading in immunocompromised patients. We present the rare case of an adolescent patient with acalculous cholecystitis due to infectious mononucleosis. The correct diagnosis was challenging due to a negative antibody test after a splenectomy he had undergone years ago.

Case Presentation
A 24-year-old Caucasian male presented to our outpatient clinic with fever and pain in the right upper abdominal quadrant. He had a history of a recent upper respiratory tract infection, which was treated with oral amoxicillin. The patient also had a history of left adrenal gland resection, distal pancreatectomy, and splenectomy due to a large pheochromocytoma two years earlier. His past medical history was otherwise unremarkable. A clinical examination revealed a tenderness in the epigastric abdomen and a cervical lymphadenopathy. An ultrasound examination revealed a thickened gallbladder wall as a sign of acute cholecystitis without 1 1 1 1 evidence of gallstones or sludge, as shown in Figure 1.

FIGURE 1: Ultrasound image of patient's gallbladder
The figure shows the patient's liver (arrow 1) and gallbladder (arrow 2) on admission day. While no stones can be found inside, the gallbladder wall (arrow 3) presents as multilayered and thickened (9.7 mm).

Discussion
Infectious mononucleosis is a common disease of the adolescent caused by EBV, a widely disseminated herpes virus type IV. About 90% to 95% of adults worldwide are EBV positive. The virus is spread by intimate contact between persons; hence, the common name "kissing disease." Less than 10% develop a clinical infection. The traditionally reported peak incidence of clinical infections lies between the age of 15 and 24 years. Most adults are immune to the infection due to prior exposure to EBV [2][3][4].
Our case was unique due to several unusual conditions. First, acalculous cholecystitis is an extremely rare complication of an EBV infection. Second, the correct diagnosis of acute mononucleosis as an underlying cause for cholecystitis was challenging due to alternated laboratory values. While the test for heterophile antibodies was positive and the patient was clearly presenting with clinical signs of infectious mononucleosis, the EBV VCA IgM was surprisingly negative at first. Remarkably, the authors found a strong response of IgG antibodies against CMV in the early phase of the infection, followed by an increased level of IgM antibodies 11 weeks after the peak of IgG antibodies. This lead to an inverted course of antibody levels compared to immunocompetent patients. In contrast to other immunodeficient states, the infections resolved spontaneously without anti-CMV therapy [5][6].
Research shows that splenectomy leads to a diminished antibody response to bacterial polysaccharide vaccines. Data suggest that the IgM response is more impaired than the IgG response. Han et al. suspected a similar mechanism in case of viral infections. This is supported by findings that show that in human blood IgM memory B cells circulate splenic marginal zone B cells. Furthermore, asplenic humans have undetectable IgM memory B cells [7][8][9].
Our patient presented in a quite similar manner to the cases Han et al. described. We found a marked lymphocytosis and an early IgG response with no initial IgM elevation. Our patient also recovered without specific antiviral therapy. We interpret this as a hint that antibody level patterns in asplenic patients infected with EBV might be similar to those in CMV.

Conclusions
This is the first reported case of infectious mononucleosis caused by EBV with acalculous cholecystitis in a patient with a history of splenectomy. Cholecystectomy is not indicated, as symptoms can be expected to resolve spontaneously. In patients with a history of splenectomy, VCA IgM antibodies can be negative in the acute phase and rise approximately two weeks after the onset of symptoms, whereas the IgG antibodies are elevated earlier. Infectious mononucleosis caused by either EBV or CMV in patients with a history of splenectomy is a rare disease. Knowledge of altered antibody patterns is crucial for a correct diagnosis.

Additional Information Disclosures
Human subjects: Consent was obtained by all participants in this study.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.